Who’s Watching the Watchdog?

With most drugs now approved through one of the FDA’s expedited-review pathways, is the agency approving drugs too quickly?

In recent years, the FDA has set new records for the number of novel drug approvals: The agency approved 48 new drugs in 2019, and in 2018 it authorized a record-breaking 59 new therapies.1 Hematology and oncology products represented a substantial portion – more than one-third – of 2019 approvals.

Many of the therapies were cleared for marketing with some type of special designation that requires the FDA to provide additional support to drug developers, expedite its review process, or consider data on surrogate endpoints to demonstrate efficacy. For example, 58% of last year’s newly approved products were reviewed through the agency’s priority review program and 44% were approved with orphan drug designation.

The goal of these programs is to get potentially helpful therapeutics to patients who could benefit from them as quickly as possible. “You can feel it. There’s excitement about the new drugs coming – and coming quickly,” Grzegorz Nowakowski, MD, Associate Professor of Medicine and Oncology and Consultant in the Hematology Division at Mayo Clinic in Rochester, Minnesota, told ASH Clinical News. Dr. Nowakowski has served on the FDA’s Oncologic Drugs Advisory Committee panels and co-chairs the American Society of Hematology (ASH) Working Group on Innovations in Clinical Trials.

But Dr. Nowakowski hinted at a potential downside of the eagerness to bring new drugs to market: With the expedited review pathways, the FDA has the flexibility to approve therapies based on less rigorous data for populations with unmet clinical need. Some stakeholders believe that looser standards mean drugs are approved too quickly, with too little data on how safe or effective they are. “With all the new approvals, there is a worry about how effective the drugs are and how they would compare with previously approved options. This is where you see differences in opinions,” he said.

With the variety of approval pathways and designations available to investigational drugs, are the implications of “FDA-approved” changing? ASH Clinical News spoke with Dr. Nowakowski and other experts in drug development about different pathways to approval and their implications for patient outcomes.

Regulatory History

In the early 20th century, the idea of regulating drugs had been floating around but never formalized, until a series of tragedies prompted the U.S. government to enact legislation to control the quality of drugs.

In 1901, a 5-year-old girl died in the hospital. An investigation revealed that, days earlier, she had received a diphtheria anti-toxin made from the blood of horses – the standard treatment at the time. Unfortunately, this shot contained serum from a horse that had died of tetanus. The toxic serum was distributed even after the horse’s death and claimed the lives of about a dozen children. At the time drugs and sera were often manufactured in local establishments without central or uniform controls to ensure potency and purity and without inspections or testing of the final product. Soon after this tragedy, Congress passed the Biologics Control Act of 1902, which introduced regulatory safeguards in the manufacturing of biological products.2

It wasn’t until several decades later, though – when more than 100 people died after being treated with a liquid formulation of sulfanilamide that had been mixed with diethylene glycol (a chemical normally used in antifreeze) – that Congress passed the 1938 Federal Food, Drug, and Cosmetic Act.3 The 1938 legislation, which requires that drugs be proven safe before they are widely used, has been modified several times but remains the basis for FDA regulation of these products.

Proving the safety and eventually the efficacy of drugs is no small task. The process of taking a drug from discovery through the clinical trials required for review can take up to a decade. Then, the FDA spends months or even years reviewing the data as it considers whether to approve a product. As this is happening, patients are waiting.

“It’s a tough spot with serious diseases like cancer,” explained S. Vincent Rajkumar, MD, Professor of Medicine and Consultant in the Division of Hematology at Mayo Clinic. “We could have a very useful drug to treat cancer, but if we are required to conduct randomized controlled trials and to show improvement in survival, in some cases that could take 10 years or longer.”

So, over the past 40 years, the FDA has devised programs to expedite the process: orphan drug, priority review, and breakthrough therapy, as well as fast track designations and the accelerated approval pathway.

“Each of these programs is designed to facilitate the development and approval of promising therapies to address unmet medical need in the treatment of serious or life-threatening conditions,” FDA spokesperson Charles Kohler told ASH Clinical News. The agency defines “filling an unmet need” as “providing a therapy where none exists or providing a therapy that may be potentially better than available therapy.”

The orphan drug program came first. Established by the Orphan Drug Act in 1983, the program incentivizes pharmaceutical companies to take the financial risk of developing drugs to treat rare diseases – those affecting fewer than 200,000 people.4 Developing these types of therapies has always been a challenge, one that wasn’t especially lucrative for companies given the small patient populations who would eventually be treated with an orphan drug. The act offered three main incentives: federal grants for orphan drug research, a 50% tax credit to help cover the cost of clinical trials, and 7 years of marketing exclusivity for products approved as orphans. However, it does not necessarily speed up the approval or access to a drug.

Taking the idea a step further, the FDA enacted its expanded access program in 1987. The program does not speed up the approval process itself but grants certain patients access to investigational drugs before they are approved, assuming the patient has no comparable alternatives and does not qualify for a clinical trial.

In 1988, as the AIDS epidemic surged in the U.S., the FDA launched its fast track program.5 According to the FDA’s guidance, this program is reserved for drugs being developed to treat or prevent a condition with no current therapy or those that may show a major advantage over other available options, such as superior effectiveness, fewer serious side effects, or improved diagnosis of a serious condition. If a therapy receives a fast track designation, it means that the FDA will be available for additional support and feedback throughout the research and application process. It also provides an opportunity for rolling review, which means that a pharmaceutical company can submit individual sections of its application as they are completed. In theory, it could speed development by identifying and resolving issues quickly, although it does not explicitly expedite the review timeline.

Four years later, the agency added the accelerated approval pathway. This is the only pathway that allows drugs to be approved based on surrogate, rather than clinical, endpoints.6 A surrogate endpoint can be a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. “For example, if a drug demonstrates a large improvement in a measure such as progression-free survival, it is likely that the drug would prolong overall survival eventually,” explained Dr. Rajkumar.

But, he added, this does not guarantee clinical benefit. Once a drug receives accelerated approval, the pharmaceutical company that manufactures it is required to complete post-market confirmatory trials to demonstrate that clinical benefit. If the trial fails to do so, a drug can be removed from the market, which rarely happens, said Alison Bateman-House, PhD, MPH, Assistant Professor in the Department of Population Health at NYU Grossman School of Medicine.

The FDA also introduced the priority review program in 1992, which sets a goal review time of 6 months – a process that typically takes about a year.7 Again, this designation is intended for drugs that would provide significant improvements in safety and efficacy over existing options. The same year, Congress also passed the Prescription Drug User Fee Act (PDUFA), allowing the agency to collect fees from drug manufacturers at the time of application submission to help fund the review process. To collect the fees, the FDA is required to meet certain performance benchmarks with respect to response time during the review process.

Most recently, in 2012, the FDA introduced the breakthrough therapy designation. If an investigational product is granted this designation, the developer receives the benefits of the fast track program, plus intensive guidance on an efficient drug development program such as the use of smaller trials with alternative designs.8 Breakthrough therapy status is given based on early clinical data using established surrogate endpoints. According to the FDA, “the primary intent of breakthrough therapy designation is to develop evidence needed to support approval as efficiently as possible.”

An investigational product can fall into more than one of these programs, but, according to Jonathan Darrow, SJD, MBA, Faculty Member of the Center for Bioethics and Assistant Professor of Medicine at Harvard Medical School, the breakthrough therapy designation is particularly appealing.

“If you want to begin to condition the market to receive your drug, to value your drug highly, to prescribe your drug, having the word ‘breakthrough’ is a great thing,” he explained. “Your application also gets special FDA attention, but much of that attention was already available through the fast track program. So, one of the main benefits of the breakthrough therapy program that’s not available through the fast track program is the name.”

  • Accelerated approval: Allows drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint
  • Breakthrough therapy: Expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
  • Fast track: Facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need
  • Priority review: Sets a goal to take action on an application within 6 months

Drug Development Timelines

Whether these new regulatory programs actually quicken the pace of approval isn’t clear. To understand their impact on drug development, Dr. Darrow and colleagues reviewed data about the number of novel drug approvals – and the speed at which they get to market – from 1983 to 2018.9

The agency’s expedited-review programs are popular: 48 of the 59 new drugs approved in 2018 benefited from the accelerated approval, fast track, or priority review designations. Since 1986, after the orphan-drug program was introduced, the time it takes for the FDA to review drug applications dropped from 2.8 years to 10.1 months for standard applications and 7.6 months for priority applications, suggesting that the newer drugs are being brought to market faster.

However, the total amount of time from when a company files an investigational new drug (IND) application – which shows that the risk-benefit ratio is likely to be reasonable enough, based on preclinical testing or experience with the drug in other clinical indications – that the drug should be tested in humans with a specific condition – to approval has remained steady, if not increased. From 1986 to 1996, the average time from authorization of clinical testing to approval was 7.8 years; between 1997 and 2007, it dipped slightly to just 7.0 years, but jumped to 9.1 years between 2008 and 2017.

While those overall average development times have stayed relatively long, drugs with breakthrough designations tend to be approved faster, in less than 5 years, the researchers noted.

Expedited or Shortsighted?

A shorter review time means patients have access to new treatments faster, but a shorter review time also means that there are fewer data upon which to base approval. Several studies have looked at whether the trade-off is worth it. For example, despite faster approvals, a 2018 study found “no evidence that these drugs provide improvements in safety or novelty [and no] statistically significant efficacy advantage when compared with non–breakthrough-designated drugs.”10

Another study, published in JAMA Network Open, looked at trends in approvals since the introduction of fast track designation and identified changes in the evidence supporting these decisions.11 Between 1995 and 1997, 81% of new drugs were approved based on at least two pivotal trials; between 2015 and 2017 the proportion approved based on at least two trials was only 53%. In addition, fewer of those trials used active comparators as opposed to a placebo or historical control arms.

However, using a smaller number of trials did not necessarily mean products were approved based on fewer data. The average number of patients the drugs were tested on remained the same. Trials also lasted longer: The proportion of drugs supported by a pivotal trial that lasted 6 or more months increased from 26% in 1995 to 46% in 2015.

Over time, explained Dr. Nowakowski, scientists have begun collecting better and better preclinical data on which to base trials. “The science that feeds the development of those drugs is much stronger than it was in the past,” he said.

Dr. Darrow argued that the number of participants in these trials is less important than the extent of benefit the trials demonstrate. “Patients’ interests are not served by the amount of evidence available, but by the amount of benefit,” he said, justifying the breakthrough therapy designation. “You don’t need to give a thousand people a parachute to know it could save a life. One is sometimes enough.”

Still, there is some evidence that when cancer drugs are approved based on data outside of randomized controlled trials, they require more safety-related label modifications.12 Of nearly 60 drugs approved between 2006 and 2016, indications not supported by randomized clinical trials were more likely to require post-approval modifications for common adverse events (odds ratio [OR] = 5.78) and major modifications in warnings and precautions (OR=4.61). “Health care professionals should be vigilant for unrecognized adverse effects when prescribing drugs approved without a supporting randomized controlled trial,” the authors concluded.

Having more participants in the trial makes it easier to show a miniscule improvement, but for rare diseases, it is difficult to find enough patients to create large control and experimental groups. To resolve that, Alan Mast, MD, PhD, Medical Director of Transfusion Medicine and Senior Investigator at Versiti Blood Center of Wisconsin and co-chair of the ASH Working Group on Innovations in Clinical Trials, noted that researchers have started using creative statistics to make sense of smaller numbers of patients. For example, “researchers can have a common control group that can be used for multiple different studies.”

Mr. Kohler from the FDA stressed that “none of the expedited programs change the evidence needed for FDA approval.”

For drugs approved through the accelerated approval pathway, though, experts suggest that the required post-market confirmatory trials are insufficient to verify a product’s clinical benefit. “The compliance of sponsors to actually do those phase IV confirmatory trials in any sort of reasonable time is fairly low,” said Dr. Bateman-House. Any time an adverse event occurs, even outside of these post-market trials, physicians are expected to report it through the FDA Adverse Event Reporting System, but she noted that under-reporting is possible.

Recruiting patients for these trials also is a challenge, especially when the drug is already available, she added. In some post-marketing trials, there is a chance the patients will get a placebo or an older therapy; if they refuse to participate, they may be able to guarantee they will get the newly approved drug.

Sometimes the trials are completed only overseas, meaning the participants are not reflective of the patients who would receive the drug in the U.S. or the control arms may not be typical for how patients are treated in the U.S., Dr. Rajkumar noted.

Pressure to Approve

The speed with which drugs are approved also raises concerns about pressure from the political arena and patient-advocacy groups.

In 2016, the FDA granted accelerated approval to eteplirsen, a muscular dystrophy drug, amid great controversy and with what was considered very limited evidence. The FDA had gone back and forth with the drug’s manufacturer, Sarepta, for months about a trial of 12 patients that suggested that the drug might increase levels of the dystrophin protein that patients lack and may have improved their performance on a 6-minute walking test.13 Muscle biopsies revealed that the drug only increased dystrophin levels an average of 0.9%. There was no placebo-controlled arm of the trial. In its decision, the FDA went against its own scientific advisors and its review panel that recommended against approval, which triggered a formal internal dispute process.

Muscular dystrophy patient advocacy groups were thrilled to have a new treatment available.14 As Dr. Bateman-House put it, “Patients may say, ‘Let me make my choices, even if it’s a risky choice. What works for the mass population may not be what works for me. Let me just have it so I can take my chances.’”

When asked about allegations that political pressure played a role in these or other approvals, Mr. Kohler stated, “The FDA is a science-based agency, and its decisions are made on the basis of science.”

Soon, however, the fact that the drug made it to market hardly mattered, as many insurance companies refused to cover the treatment, which cost $300,000 and which payers felt had too little evidence to support its efficacy.15 Patients without the means to pay continued to be unable to access it, and some patients set up GoFundMe accounts to try to raise the money. “This is a classic example of why it is so important that we have robust evidence, not only for patients’ health, but also for their economic well-being,” said Dr. Bateman-House.

Post-market confirmatory trials are planned for eteplirsen but have been delayed, and results are not expected until 2024.

In the hematology arena, the accelerated approval of the drug selinexor incited a similar debate over limited data in 2019 when it was approved for myeloma, and then in 2020 when it received an additional indication for diffuse large B-cell lymphoma (DLBCL). Regarding the DLBCL approval, critics contested that the treatment is associated with only modest activity and high adverse event burden, with an unknown effect on survival or quality of life.

“There are no direct comparisons of the toxicity profiles of selinexor versus other conventional therapies, but based on the toxicities described with selinexor in the STORM trial for relapsed/refractory myeloma and the SADAL trial in DLBCL, it is likely that gastrointestinal toxicities are more frequent with selinexor than with other commonly used regimens,” said David Iberri, MD, of Stanford Medicine in California, when asked to comment on the findings of the SADAL trial.16 The pivotal SADAL trial also had a primary endpoint of overall response rate, meaning that, until longer-term and comparative data are available, “clinicians lack the data necessary to have an informed discussion with patients regarding potential benefits and risks of selinexor versus other regimens,” he added. “In my opinion, FDA approval should have been deferred until efficacy could be confirmed in a randomized phase III study with the primary endpoint of overall survival.”

What Does the Future Hold?

Not all experts agreed on where the FDA is headed or if the recent controversies signal a permanent loosening of restrictions. Some researchers who spoke with ASH Clinical News predicted that the agency is unlikely to make major adjustments to the approval process anytime soon, while others think that the group may add restrictions that lengthen the time it takes for drugs to make it to market.

“Commenters have noted FDA’s increasing use of accelerated programs over the past decade, often with a view that the increase is driven by a loosening of our approval standards,” said Mr. Kohler. “In reality, the FDA’s standards have not changed. Instead, the increased use of expedited approval pathways is directly related to the increasing numbers and scope of these programs provided by Congress, as well as the kinds of medicines that are being developed and the types of diseases that are being studied.”

Dr. Rajkumar echoed that statement, pointing out that, with the exception of the breakthrough therapy designation, the approval pathways and designations haven’t changed in more than a decade. “We now have more drugs going through the pathway, but the processes are the same as they have always been,” he said.

As it has done for every other aspect of life, however, the COVID-19 pandemic has led to a reappraisal of priorities in the drug approval arena: In June, three Republican senators introduced the Promising Pathways Act, which “requires the FDA to establish a rolling, real-time, priority review pathway to evaluate provisional approval applications for drugs intended to treat, prevent, or diagnose serious or life-threatening diseases or conditions – including those that pose a threat of epidemic or pandemic (e.g., COVID-19).”17

Others have advocated for reform at the FDA. In a commentary accompanying Dr. Darrow’s 2020 analysis, Joshua Sharfstein, MD, Vice Dean for Public Health Practice and Community Engagement at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, laid out four steps to improve the U.S. drug approval system.18 First, he argues, the FDA and Congress need to revise the existing pathways to promote more meaningful competition for orphan drugs being used for non-orphan diseases and to ensure that drugs that receive fast track and breakthrough therapy designations are highly likely to produce major clinical advances for patients.

“The FDA’s standards have not changed. … The increased use of expedited approval pathways is directly related to the increasing numbers and scope of these programs provided by Congress.”

—Charles Kohler, FDA spokesperson

Next, the FDA should strengthen its oversight of post-market studies. Third and fourth, he wrote, the FDA should reconsider its special marketing exclusivity incentives, some of which end up being extremely expensive. The incentives could be made conditional on the completion of post-market trials to incentivize pharmaceutical companies to complete them in a timely manner.

Dr. Darrow said that Congress tends to tighten requirements on medicines as a response to tragedy and loosen them between tragedies. “There’s a long history of the FDA of responding to tragedy: The 1902 Biologics Control Act was passed after people died based on tainted antiserum. The 1937 act was passed after people died from a poisonous antibiotic. More recently, we’ve seen tightened regulation following compounding errors [in pharmacies] that led to contamination and a number of deaths,” he said. “But, between all of those tragedies, there has been pressure to relax the requirements.”

In the near future, he said, “I would expect that there will be a continued trend to relax requirements until the next tragedy occurs. It’s unfortunate, but that’s what history has shown us.” —By Emma Yasinski


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    FDA. The Road to the Biotech Revolution – Highlights of 100 Years of Biologics Regulation. Accessed October 8, 2020, from https://www.fda.gov/about-fda/histories-product-regulation/road-biotech-revolution-highlights-100-years-biologics-regulation.
  2. FDA. Sulfanilamide Disaster. Accessed October 8, 2020, from https://www.fda.gov/files/about%20fda/published/The-Sulfanilamide-Disaster.pdf.
  3. FDA. Orphan Drug Act – Relevant Excerpts. Accessed October 8, 2020, from https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/orphan-drug-act-relevant-excerpts.
  4. FDA. Fast Track. Accessed October 8, 2020, from https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track.
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  6. FDA. Priority Review. Accessed October 8, 2020, from https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review.
  7. FDA. Breakthrough Therapy. Accessed October 8, 2020, from https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy.
  8. Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323:164-176.
  9. Hwang TJ, Franklin JM, Chen CT, et al. Efficacy, safety, and regulatory approval of Food and Drug Administration–designated breakthrough and nonbreakthrough cancer medicines. J Clin Oncol. 2018;36:1805-1812.
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  12. Undark. FDA documents reveal depths of internal rancor over drug’s approval process. August 2, 2017. Accessed October 8, 2020, from https://undark.org/2017/08/02/fda-eteplirsen-janet-woodcock/.
  13. Parent Project Muscular Dystrophy (PPMD). PPMD applauds FDA for landmark approval of first-ever disease-modifying drug to treat Duchenne muscular dystrophy. Accessed October 8, 2020, from https://www.prnewswire.com/news-releases/ppmd-applauds-fda-for-landmark-approval-of-first-ever-disease-modifying-drug-to-treat-duchenne-muscular-dystrophy-300330263.html.
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  15. ASH Clinical News. Evaluating selinexor in patients with relapsed/Refractory DLBCL. September 1, 2020. Accessed October 8, 2020, from https://www.ashclinicalnews.org/news/literature-scan/evaluating-selinexor-patients-relapsed-refractory-dlbcl/4/.
  16. Mike Braun Senate website. Senator Braun & colleagues introduce Promising Pathway Act for patients with serious and life-threatening illnesses. June 4, 2020. Accessed October 8, 2020, from https://www.braun.senate.gov/senator-braun-colleagues-introduce-promising-pathway-act-patients-serious-and-life-threatening.
  17. Sharfstein JM. Reform at the FDA—in need of reform. JAMA. 2020;323:123-124.

Aside from review benchmarks associated with the accelerated-approval pathway, a recent analysis found that the FDA may be implementing its own internal deadlines to quickly approve drugs. Unfortunately, these pressures may be related to more safety events.

“Absent explicit quotas, incentives, reporting, or fiscal year-end motives, drug approvals around the world surge in December, at month-ends, and before respective major national holidays,” the researchers wrote. For example, looking at approvals between 1980 and 2016, they found that approximately 15% of all new drugs are approved in December, an increase of around 80% relative to the average month.

The burst of activity has an unintended side effect: End-of-year approvals were eventually associated with more hospitalizations, life-threatening incidents, and deaths.

While they concluded that drugs approved at the end of the year should receive additional scrutiny, the authors noted that their analysis was based on absolute counts of drug approvals and adverse events. This means that they were unable to determine how many people used a drug or how many people benefited from having access to it.

Source: Cohen L, Gurun U, Li D. Internal deadlines, drug approvals, and safety problems. SSRN preprint. July 30, 2019. Accessed October 8, 2020 from https://ssrn.com/abstract=3427338.